This proposal represents an application to continue the applicant's training and research in the genetic epidemiology of psychiatric disorders in general and the affective disorders, in particular. The methods of genetic epidemiology will be applied: at both the level of the phenotype, to provide more accurate specification of the boundaries of the affective disorders and their association with several comorbid psychiatric and non-psychiatric disorders; and at the level of the genotype, to examine the role of factors related to non-penetrance (i.e., lack of gene expression in susceptible persons) and vulnerability and protective factors in persons at risk for affective disorders by virtue of possessing a linkage marker. Proposed training includes: acquiring experience in the conduct of linkage analysis; gaining understanding of the laboratory methods of molecular biology including characterization of RFLP's, candidate genes and their m-RNA products; and receiving supervision and consultation in the application of longitudinal analysis and appropriate statistical methods for assessing mechanisms for diagnostic overlap between disorders. Data from five studies will be employed to accomplish the above aims: (1) a family study of the comorbidity of affective disorders, anxiety disorders, and substance abuse; (2) a prospective study of children at risk for the latter disorders; (3) an epidemiologic prospective longitudinal cohort study of young adults from Zurich Switzerland; (4) a large longitudinal epidemiologic study of health in the U.S. adult population; and (5) a family study of comorbidity of affective disorders and migraine headache. Despite the complexity of the major psychiatric disorders, the application of family studies with a specific goal of studying the mechanisms for associations between disorders which have been found to be comorbid to the affective disorders at the population level through the analysis of their co-segregation, and longitudinal course, may help to elucidate clearer specification of their definitions. more accurate phenotypic definitions will dramatically increase the power of linkage studies to yield markers with which to identify individuals-at-risk, as well as environmental factors that may lead to protection from expression of the underlying vulnerability.